The invention relates to a new therapeutic use of benzhydrylsulphinyl derivatives.
More particularly, it relates to the use of such derivatives in situations of disorders in vigilance associated with an anti-pain treatment as applied in cases of serious diseases such as cancer, or for the painful after-effects of serious conditions.
About 40% of cancer patients have in fact to face pain in the course of the evolution of their disease.
This occurs either due to the unfavourable progression of the cancer, or due to the after-effects of the various treatments undertaken.
Several years ago the World Health Organization established a certain number of principles for dealing with pain in cancerology. In particular, it noted the important place which morphine should occupy in this treatment.
Thanks to this impetus and in spite of the cultural prejudices revolving around morphine, this product is now prescribed and accepted more and more readily.
Although its high efficacy on the analgesic level no longer has to be demonstrated, its side effects cannot be ignored, in particular the sleepiness which it causes. The various studies which have evaluated it report that it inconveniences 30 to 50% of patients under morphine
where this is taken in the context of chronic treatment of cancer.
Current research approaches in the treatment of pain are mostly orientated towards the prospect of reducing these side effects, and in particular sleepiness.
The products available to the clinician to date are essentially amphetamine derivatives. However, such derivatives are the source of major disadvantages associated with their undesirable cardiovascular and neuropsychic effects on the one hand, and dependence during long-term use on the other hand.
In investigating a solution to this problem, the inventors orientated themselves towards evaluation of the effects, in the context of morphine treatment, of compounds known for their awakening power and their ability to stimulate vigilance.
They were thus able to demonstrate unexpectedly that such compounds selectively antagonized the hypnogenic effect of morphine without affecting its analgesic activity and without creating other disadvantages.
It has also been demonstrated that these selective antagonist effects were also exerted on the sleepiness states induced by medicaments conventionally administered with morphine, such as analgesics, antidepressants and anxiolytics.
The invention thus provides the use for the manufacture of medicaments of compounds which are capable of exerting an awakening effect in situations of disorders in vigilance associated with a morphine treatment (this expression encompassing the use of morphine or derivatives
thereof with, where appropriate, the medicaments usually used in this type of context).
It also provides new pharmaceutical presentations which allow all the required effects to be obtained conjointly.
According to the invention, benzhydrylsulphinyl compounds corresponding to the general formula (I) 
in which
each of the rings can be substituted by one or more F, Cl, Br, CF3, NO2, NH2, C1-C4-alkyl, C1-C4-alkoxy or methylenedioxy groups;
R represents a hydroxyl group, a hydrogen atom, a C1-C4-alkyl group, a C1-C4-hydroxyalkyl group or a R1R2Nxe2x80x94Yxe2x80x94 group, where Y is a linear or branched C1-C4 -hydrocarbon radical, and R1 and R2 are identical or different and each represent a hydrogen or a C1 to C4-alkyl or NR1R2 represents a 5- or 6-membered heterocyclic radical containing, where appropriate, a second heteroatom such as N or O, and which can be substituted;
n is an integer equal to 1, 2 or 3; and their addition salts when R contains a basic radical,
are used for the manufacture of the said medicaments.
Preferably, R represents an xe2x80x94OH group or a hydrogen atom.
The invention particularly provides the use of benzhydrylsulphinyl-acetohydroxamic acid of the formula (II) 
called adrafinil by its international nonproprietary name and marketed under the brand name Olmifon(copyright).
It more particularly provides the use of its metabolite, that is to say benzhydrylsulphinyl-acetamide of the formula (III) 
corresponding to the international nonproprietary name modafinil and marketed under the brand name Modiodal(copyright).
The compounds used according to the invention are known for their selective stimulating activity on awakening and vigilance and are widely used for treatment of narcolepsy and idiopathic hypersomnia.
Surprisingly, when used in the context of morphine treatment, combined, where appropriate, with administration of antidepressants and/or anxiolytics and/or analgesics, they allow a considerable reduction in the state of sleepiness evaluated by
the Epworth scale, while ensuring the analgesic properties of morphine and the properties of antidepressant, anxiolytic or analgesic medicaments are maintained. The patient is thus re-established in a satisfactory relational life.
According to an advantageous embodiment of the invention, the said medicaments comprise at least one compound of the formula (I) in an amount of 50 to 600 mg, preferably 100 to 300 mg.
During preparation of the medicaments, the active principles are mixed with pharmaceutically acceptable vehicles for the chosen mode of administration.
For administration by the oral route, the medicaments are thus prepared in the form of gelatine capsules, tablets, coated tablets, capsules and analogous products.
For administration by the injectable route, the medicaments are in the form of solutions in injectable ampoules.
Administration by the transcutaneous route, in the form of a patch, can also be used.
As shown in the examples, very favourable results were obtained clinically with administrations of about 200 to 400 mg Modiodal(copyright) per day, in 1 or 2 doses, and about 1,200 to 1,800 mg Olmifon(copyright) per day, in 2 doses.
According to another aspect utilizing the effects resulting from conjoint administration of analgesics and/or antidepressants and/or anxiolytics on the one hand and products which stimulate vigilance on the other hand, the invention provides a pharmaceutical presentation, characterized in that it comprises the two
types of medicaments respectively, with a suitable information leaflet.
In this presentation, the medicaments are in galenical forms suitable for the chosen administration route.
In order to illustrate the invention, but without limiting its scope, the results of observations made confidentially on patients in the context of hospitalization are reported below. The consent of the patients was obtained after the compassionate grounds of the prescription had been explained to them.